Researchers from IISER Pune have designed and synthesized new compounds that can release sulphur dioxide and slow the growth of Mycobacterium tuberculosis, the pathogenic bacterium causing tuberculosis. This work, published in the Journal of Medicinal Chemistry (55:553-557), presents a new candidate drug in the treatment of the disease.
Given the concern that drug resistant variants of pathogenic bacteria cause in patients, medical community and policy makers, identifying new, improved candidate drugs is a constant need. Tuberculosis affects millions of people every year and current drugs used to treat the disease have been in the market for a number of years. “There is limited interest in developing new drugs against tuberculosis as it is often not considered a profitable market. The fact that as few as about six candidate drugs are presently in clinical trials for tuberculosis suggests the need to identify additional candidates,” says Harinath Chakrapani, lead author on this study and principal investigator at IISER Pune.
Chakrapani and his group to explore the possibility of using sulphur dioxide (SO2) against these bacteria. “Here is a gas that can cause damage to cells at higher concentrations, but is present in certain meats and is routinely used in wine-making. This means that the compound can be tolerated to a certain extent by human body. We thought it is then worthwhile to check what its effects might be on bacteria causing tuberculosis,” reasons Chakrapani.
Having taken this approach, one of the main challenges was to develop compounds that can release sulphur dioxide inside cells in a controlled manner. To this end, the authors synthesized various derivatives of 2,4-dinitrosulfonamide (2,4-DNS) with the idea that suphur dioxide gets released when 2,4-DNS or its analogues react with thiols present in cells. They were hoping that the nature of the varying group on the amine of 2,4-DNS would regulate the rate of sulphur dioxide release.
The authors propose a thiol (RSH) based mechanism for the release of sulphur dioxide (SO2) from a 2,4-DNS derivative (see Figure).
The synthesized compounds were tested in two aspects: ability to release sulphur dioxide in test tube in the presence of an external thiol, such as cysteine; and ability to slow the growth of mycobacterium tuberculosis. The authors found a positive correlation, i.e., those compounds which could release SO2 in a test tube reaction were also able to slow the growth of tuberculosis bacteria.
Much to the excitement of the authors, one of the compounds they tested could slow bacterial growth at an even lower concentration than that of isoniazid, a routinely used drug in the treatment of tuberculosis. Importantly, this new compound was found be 50 times more effective on bacterial cells than on human cells.
Chakrapani and his group are interested in exploring the mechanism by which these new compounds affect the growth of Mycobacterium tuberculosis even as their initial results suggest a two-way mechanism that includes action of sulphur dioxide as well as depletion of cellular thiols. Their recent results (accepted for publication in Bioorganic & Medicinal Chemistry Letters) show a strong correlation between the rate of sulphur dioxide generation and the minimum concentration of the candidate molecule required to slow bacterial growth.
This study “Design, synthesis, and evaluation of thiol-activated sources of sulfur dioxide (SO2) as antimycobacterial agents” has been published in the Journal of Medicinal Chemistry (55:553-557) and is authored by Satish Malwal, Dharmarajan Sriram, Perumal Yogeeswari, Badireenath Konkimalla, and Harinath Chakrapani.
This research is supported by funds from IISER Pune, NISER Bhubaneshwar, and the Department of Science and Technology (DST) India.
–Reported by Shanti Kalipatnapu